Biology:NLRP3

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NLR family pyrin domain containing 3 (NLRP3) is a protein that in humans is encoded by the NLRP3 gene[1] located on the long arm of chromosome 1.[2] NLRP3 has previously been known as NACHT, LRR, and PYD domains-containing protein 3 [NALP3]; cryopyrin; cold induced autoinflammatory syndrome 1 (CIAS1), caterpillar-like receptor 1.1 (CLR1.1), and PYRIN-containing APAF1-like protein 1 (PYPAF1).[3]

NLRP3 is a component of the innate immune system that functions as a pattern recognition receptor (PRR) – a cytosolic sensor that responds to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). NLRP3 belongs to the NOD-like receptor (NLR) family of PRRs.[4]

NLRP3 is expressed predominantly in macrophages, where it serves as a component of the inflammasome.[5][6] The NLPR3 inflammasome triggers inflammation and an immune response, and causes cell death through pyroptosis or PANoptosis.[7] Since its discovery in 2004, the NLRP3 inflammasome has emerged as a critical component of innate immunity, and mutations in the NLRP3 gene have been associated with a number of organ-specific autoimmune diseases, autoinflammatory diseases, and cancers. Hence, the NLRP3 inflammasome has become the best-understood inflammasome and a central focus of inflammation research.

Structure

The domain structure of NLRP3 is reflected in its full name, nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3. The protein contains an N-terminus pyrin domain (PYD), a NACHT domain containing a nucleotide-binding site (NBS), and a C-terminus LRR motif. NACHT, LRR, and PYD are acronyms for:

Available cryogenic electron microscopy (cryo-EM) structures suggest that in its inactive state, NLRP3 forms a ring- or disc-shaped oligomer in which the LRRs interact to form a cage that protects the PYDs. On activation, it is thought that NLRP3 undergoes a conformational change that exposes the PYDs,[10][11] and the PYD of NLRP3 then interacts with the PYD of an adaptor protein known as apoptosis-associated speck-like protein containing a CARD (ASC).[10] Proteins containing the caspase recruitment domain, CARD, have been shown to be widely involved in inflammation and immune response.[1]

Activation Mechanisms

NLRP3 activation occurs in response to danger signals — PAMPs (such as viral RNA or proteins[12]), DAMPs (such as crystalline uric acid or extracellular ATP released by damaged cells[13]), or other homeostatic disruptions.[14] However, there is currently no unifying mechanism of activation, and it is unclear if NLRP3 binds a specific ligand or responds more generally to a loss of homeostasis.[15]

Many different activation and regulatory mechanisms have been identified for context-dependent NLRP3 activation. In the absence of an activating signal, some studies have suggested that NLRP3 is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. Under certain circumstances, NLRP3 can be primed for activation by a decrease in intracellular potassium (K+) levels[16] caused by efflux from mechanosensitive ion channels located in the cell membrane.[17] However, other triggers induce NLRP3 activation through K+-independent immune signaling,[15][18] suggesting this is not a universal mechanism. Reactive oxygen species (ROS) can also contribute to activation, though the precise mechanisms of such regulation has not been determined.[19] It is likely that activation involves several organelles, including the mitochondria and trans-Golgi network, but a comprehensive overall picture of NLRP3 organelle dynamics has not yet emerged.[11] Post-translational modifications also play a role in the regulation of NLRP3.[20] The best-known of these is phosphorylation by NIMA-related kinase 7 (NEK7), which is essential for NLRP3 activation in mice, though not in humans.[10]

Regardless of the specific activation mechanism, the activation of NLRP3 allows it to bind the adaptor protein ASC to form a caspase-1-activating complex known as the NLRP3 inflammasome.

Function

NLRP3 functions primarily through its inflammasome. ASC is thought to act as an adaptor protein, oligomerizing into a fibril that extends from the center of the NLRP3 ring[10] to yield complexes ~1 μm in diameter.[21] This structure then nucleates the other components of the inflammasome.

The C-terminal CARDs of fibrillar ASC bind procaspase-1 molecules, which autoactivate by cleavage into the active protease caspase-1.[22] NLRP3-mediated caspase-1 activation plays two major roles in innate immunity: it activates the inflammatory cytokines IL-1β and IL-18,[23] and it activates gasdermin D.[24] The cleaved, active subunit of gasdermin D then oligomerizes to form plasma membrane pores that preferentially release activated IL-1β and IL-18.[25]

Besides mediating cytokine release, the NLRP3 inflammasome is also an important mediator of inflammatory, lytic cell death. When membrane pore formation and lysis occur as the end point of cell death, further cytokines and DAMPs are released, strengthening the inflammatory response.[26] NLRP3-mediated cell death has conventionally been attributed to pyroptosis, a form of inflammatory cell death that is fully dependent on caspase-1. However, NLRP3-mediated cell death can alternatively occur through PANoptosis,[27] a distinct innate immune, inflammatory cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting serine/threonine-protein kinases (RIPKs) 1 and 3.[24] NLRP3 can act as a PANoptosis sensor, but it and its inflammasome components have also been identified as components of PANoptosomes (immune complexes mediating PANoptosis) associated with the sensor molecules NLRP12, NLRC5, and ZBP1.[24]

Through its roles in driving cytokine release and inflammatory cell death, NLRP3 is central in host defense. The NLRP3 inflammasome is activated in response to pathogens including bacteria, viruses, and fungi.[28] For example, among bacteria, it has been suggested that NLRP3 provides protection against Staphylococcus aureus and Salmonella,[28] and against Streptococcus pneumoniae infections by activating STAT6 and SPDEF.[29] Among viruses, it has been associated with infection by hepatitis B virus, SARS-CoV-2, influenza virus, and human immunodeficiency virus (HIV).[28]

Beyond infection, NLRP3 also mediates the death of cancerous cells in some contexts, including in some studies of colorectal cancer,[30] and a study of hepatocellular carcinoma found the components of the NLRP3 inflammasome are downregulated or absent.[31]

Pathology

Despite the beneficial functions of the NLRP3 inflammasome, dysregulation is associated with pathogenesis in a wide range of diseases and cancer.[28][30][32] In particular, mutations in the NLRP3 gene result in autoactive inflammasomes[33] — indeed, NLRP3 was originally discovered through its mutation that causes cryopyrin-associated periodic syndrome (CAPS),[34] a spectrum of dominantly inherited, NLRP3-associated autoinflammatory diseases that includes familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal onset multisystem inflammatory disease (NOMID), and keratoendotheliitis fugax hereditaria.[1][35] In addition, dysregulated NLRP3 activity has a role in the pathogenesis of gout,[13] hemorrhagic stroke[36] and neuroinflammation occurring in protein-misfolding diseases such as Alzheimer's, Parkinson's, and prion diseases.[37][38][39] Deletion of Nlrp3 or other inflammasome components has been shown to ameliorate disease in mouse models for gout, type 2 diabetes, multiple sclerosis, Alzheimer's disease, and atherosclerosis.[40] Furthermore, during infection, overactivation of the NLRP3 inflammasome can cause excess inflammation and pathology.[28]

In the context of cancer, studies have shown roles for NLRP3 in cancer suppression for specific malignancies, yet NLRP3 and the NLRP3 inflammasome are positively associated with tumorigenesis in other cancers.[30][32] For example, high NLRP3 and/or NLRP3 inflammasome expression has been observed in cancerous tissue in pancreatic ductal adenocarcinoma (PDAC), melanoma cells, acute myeloid leukemia, and other cancer types.[30][32]

Inhibition

Through its widespread roles in driving cell death, inflammation, and pathogenesis, the NLRP3 inflammasome has garnered attention as a potential drug target for a variety of diseases underpinned by inflammation, and numerous inhibitors have been investigated.[41][42][43] The diarylsulfonylurea MCC950 was considered particularly promising as a potent and selective NLRP3 inhibitor[44] that is able to lock the inactive NLRP3 structure.[45] However, Phase II clinical trials identified possible signs of liver toxicity.[46] Nodthera and Inflazome, have entered phase I clinical trials, and Dapansutrile (OLT1177), a β-sulfonyl nitrile molecule compound developed by Olactec Therapeutics, has been evaluated in clinical trials as a selective NLRP3 inhibitor for treating heart failure, osteoarthritis and gouty arthritis.[47] No inhibitor has yet been approved for clinical use.

An alternative approach to inhibiting NLRP3 is to inhibit its upstream activation or downstream signaling. For example, the metabolite β-hydroxybutyrate has been shown to block NLRP3-mediated inflammatory disease in preclinical models by preventing K+ efflux.[48] Other inhibitors to target gasdermin D and IL-1β have also been evaluated, and IL-1β blockade has proven to be clinically efficacious in a number of diseases, particularly CAPS.[49] There remains an urgent need to identify effective inhibitors that can be used in larger patient populations. Efforts to target NLRP3 and its inflammatory mediators have gained considerable momentum, and the development of new inhibitors remains a dynamic field.

References and notes

  1. ↑ 1.0 1.1 1.2 Anon. (2015). "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3 [Homo sapiens (human), Gene ID: 114548 (updated on 13-Nov-2015)"]. Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=114548. 
  2. ↑ "Identification of a locus on chromosome 1q44 for familial cold urticaria". American Journal of Human Genetics 66 (5): 1693–1698. May 2000. doi:10.1086/302874. PMID 10741953. 
  3. ↑ Q96P20
  4. ↑ 4.0 4.1 "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". Journal of Immunology 183 (12): 7623–7629. December 2009. doi:10.4049/jimmunol.0902425. PMID 20007570. 
  5. ↑ "P2X7R: a potential key regulator of acute gouty arthritis". Seminars in Arthritis and Rheumatism 43 (3): 376–380. December 2013. doi:10.1016/j.semarthrit.2013.04.007. PMID 23786870. 
  6. ↑ "Structural mechanisms of inflammasome assembly". The FEBS Journal 282 (3): 435–444. February 2015. doi:10.1111/febs.13133. PMID 25354325. 
  7. ↑ "Inflammasomes and their role in PANoptosomes". Current Opinion in Immunology 91. December 2024. doi:10.1016/j.coi.2024.102489. PMID 39340880. 
  8. ↑ "The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation". Trends in Biochemical Sciences 25 (5): 223–224. May 2000. doi:10.1016/S0968-0004(00)01577-2. PMID 10782090. 
  9. ↑ "The PYRIN domain: a novel motif found in apoptosis and inflammation proteins". Cell Death and Differentiation 7 (12): 1273–1274. December 2000. doi:10.1038/sj.cdd.4400774. PMID 11270363. 
  10. ↑ 10.0 10.1 10.2 10.3 "Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation". Annual Review of Immunology 41 (1): 301–316. April 2023. doi:10.1146/annurev-immunol-081022-021207. PMID 36750315. 
  11. ↑ 11.0 11.1 "The NLRP3 inflammasome: activation and regulation". Trends in Biochemical Sciences 48 (4): 331–344. April 2023. doi:10.1016/j.tibs.2022.10.002. PMID 36336552. 
  12. ↑ "NLRP3 Inflammasome-A Key Player in Antiviral Responses". Frontiers in Immunology 11. 2020-02-18. doi:10.3389/fimmu.2020.00211. PMID 32133002. 
  13. ↑ 13.0 13.1 "Detection of immune danger signals by NALP3". Journal of Leukocyte Biology 83 (3): 507–511. March 2008. doi:10.1189/jlb.0607362. PMID 17982111. 
  14. ↑ "The NLRP3 inflammasome: molecular activation and regulation to therapeutics". Nature Reviews. Immunology 19 (8): 477–489. August 2019. doi:10.1038/s41577-019-0165-0. PMID 31036962. 
  15. ↑ 15.0 15.1 "Toward targeting inflammasomes: insights into their regulation and activation". Cell Research 30 (4): 315–327. April 2020. doi:10.1038/s41422-020-0295-8. PMID 32152420. 
  16. ↑ "Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation". Science Advances 7 (38). September 2021. doi:10.1126/sciadv.abf4468. PMID 34524838. Bibcode: 2021SciA....7.4468T. 
  17. ↑ "Activation of NLRP3 inflammasome by crystalline structures via cell surface contact". Scientific Reports 4. December 2014. doi:10.1038/srep07281. PMID 25445147. Bibcode: 2014NatSR...4.7281H. 
  18. ↑ "NLRP3 inflammasome activation and cell death". Cellular & Molecular Immunology 18 (9): 2114–2127. September 2021. doi:10.1038/s41423-021-00740-6. PMID 34321623. 
  19. ↑ "Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments". Current Opinion in Immunology 25 (1): 40–45. February 2013. doi:10.1016/j.coi.2012.12.004. PMID 23305783. 
  20. ↑ "Regulation of the NLRP3 Inflammasome by Post-Translational Modifications and Small Molecules". Frontiers in Immunology 11. 2021-02-02. doi:10.3389/fimmu.2020.618231. PMID 33603747. 
  21. ↑ "What are NLRP3-ASC specks? an experimental progress of 22 years of inflammasome research". Frontiers in Immunology 14. 2023-07-26. doi:10.3389/fimmu.2023.1188864. PMID 37564644. 
  22. ↑ "The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis". Nature Immunology 10 (3): 241–247. March 2009. doi:10.1038/ni.1703. PMID 19221555. 
  23. ↑ "Caspase activation without death". Cell Death and Differentiation 6 (11): 1075–1080. November 1999. doi:10.1038/sj.cdd.4400596. PMID 10578176. 
  24. ↑ 24.0 24.1 24.2 "The NLR family of innate immune and cell death sensors". Immunity 57 (4): 674–699. April 2024. doi:10.1016/j.immuni.2024.03.012. PMID 38599165. 
  25. ↑ "Gasdermin D pore structure reveals preferential release of mature interleukin-1". Nature 593 (7860): 607–611. May 2021. doi:10.1038/s41586-021-03478-3. PMID 33883744. Bibcode: 2021Natur.593..607X. 
  26. ↑ "Innate immune sensing of cell death in disease and therapeutics". Nature Cell Biology 26 (9): 1420–1433. September 2024. doi:10.1038/s41556-024-01491-y. PMID 39223376. 
  27. ↑ "Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease". Cell Discovery 11 (1). May 2025. doi:10.1038/s41421-025-00791-3. PMID 40325022. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 "NLRP3 Inflammasomes: Dual Function in Infectious Diseases". Journal of Immunology 213 (4): 407–417. August 2024. doi:10.4049/jimmunol.2300745. PMID 39102612. 
  29. ↑ "ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism". Mucosal Immunology 12 (5): 1092–1103. September 2019. doi:10.1038/s41385-019-0181-1. PMID 31278375. 
  30. ↑ 30.0 30.1 30.2 30.3 "NLRP3 and cancer: Pathogenesis and therapeutic opportunities". Pharmacology & Therapeutics 251. November 2023. doi:10.1016/j.pharmthera.2023.108545. PMID 37866732. 
  31. ↑ "Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression". Laboratory Investigation; A Journal of Technical Methods and Pathology 94 (1): 52–62. January 2014. doi:10.1038/labinvest.2013.126. PMID 24166187. 
  32. ↑ 32.0 32.1 32.2 "NLRP3 inflammasome in cancer and metabolic diseases". Nature Immunology 22 (5): 550–559. May 2021. doi:10.1038/s41590-021-00886-5. PMID 33707781. 
  33. ↑ "Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production". Nature Communications 15 (1). February 2024. doi:10.1038/s41467-024-44990-0. PMID 38321014. Bibcode: 2024NatCo..15.1096M. 
  34. ↑ "The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity". Immunological Reviews 322 (1): 259–282. March 2024. doi:10.1111/imr.13292. PMID 38146057. 
  35. ↑ "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology 188: 41–50. April 2018. doi:10.1016/j.ajo.2018.01.017. PMID 29366613. 
  36. ↑ "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". Journal of Cerebral Blood Flow and Metabolism 40 (9): 1752–1768. September 2020. doi:10.1177/0271678X20923551. PMID 32423330. 
  37. ↑ "Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome". Immunology and Cell Biology 88 (1): 20–23. January 2010. doi:10.1038/icb.2009.93. PMID 19935768. 
  38. ↑ "NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice". Nature 493 (7434): 674–678. January 2013. doi:10.1038/nature11729. PMID 23254930. Bibcode: 2013Natur.493..674H. 
  39. ↑ "NALP3 inflammasome activation in protein misfolding diseases". Life Sciences 135: 9–14. August 2015. doi:10.1016/j.lfs.2015.05.011. PMID 26037399. 
  40. ↑ "Taming the inflammasome". Nature Medicine 21 (3): 213–215. March 2015. doi:10.1038/nm.3808. PMID 25742454. 
  41. ↑ "Pharmacological Inhibitors of the NLRP3 Inflammasome". Frontiers in Immunology 10. 2019-10-25. doi:10.3389/fimmu.2019.02538. PMID 31749805. 
  42. ↑ "Pharma Looks to Inflammasome Inhibitors as All-Around Therapies" (in en). https://www.the-scientist.com/pharma-looks-to-inflammasome-inhibitors-as-all-around-therapies-68582. 
  43. ↑ "INFLAMMASOME INHIBITORS - 21st Century Miracle Drugs: Spotlight on Clinical NLRP3 Inflammasome Inhibitors" (in en-US). 2023-04-03. https://drug-dev.com/inglammasome-inhibitors-21st-century-miracle-drugs-spotlight-on-clinical-nlrp3-inflammasome-inhibitors/. 
  44. ↑ "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases". Nature Medicine 21 (3): 248–255. March 2015. doi:10.1038/nm.3806. PMID 25686105. Bibcode: 2015NatMe..21..248C. 
  45. ↑ "MCC950 closes the active conformation of NLRP3 to an inactive state". Nature Chemical Biology 15 (6): 560–564. June 2019. doi:10.1038/s41589-019-0278-6. PMID 31086329. 
  46. ↑ "Targeting the NLRP3 inflammasome in inflammatory diseases". Nature Reviews. Drug Discovery 17 (8): 588–606. August 2018. doi:10.1038/nrd.2018.97. PMID 30026524. Bibcode: 2018NRvDD..17..588M. 
  47. ↑ "Dapansutrile". Alzheimer's Drug Discovery Foundation. https://www.alzdiscovery.org/uploads/cognitive_vitality_media/Dapansutrile-Cognitive-Vitality-For-Researchers.pdf. 
  48. ↑ "The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease". Nature Medicine 21 (3): 263–269. March 2015. doi:10.1038/nm.3804. PMID 25686106. 
  49. ↑ "Blocking interleukin-1β in acute and chronic autoinflammatory diseases". Journal of Internal Medicine 269 (1): 16–28. January 2011. doi:10.1111/j.1365-2796.2010.02313.x. PMID 21158974. 
  • Overview of all the structural information available in the PDB for UniProt: Q96P20 (NACHT, LRR and PYD domains-containing protein 3) at the PDBe-KB.

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